Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
Esters of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid are useful as intermediates in the synthesis of compounds that have utility, for example, as pharmaceuticals. For example, (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]-hexane-2-carboxylic acid, methyl ester hydrochloride is disclosed in US Publication No. 2003-0216325 A1 which is incorporated herein by reference. This compound is a key intermediate used in preparation of the hepatitis C virus (“HCV”) protease inhibitor having the following structure of formula Z:

The compound of formula Z is useful for treating hepatitis C and related disorders. Specifically, the compound of formula Z is an inhibitor of the HCV NS3/NS4a serine protease.
Various methods are known in the art to make esters of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, which have the formula

where R is, for example, alkyl, aryl, aralkyl, cycloalkyl and cycloalkylalkyl.
For example, US Publication No. 2003-0216325 A1 discloses preparation of compound 1
from the corresponding alcohol 2
by performing a Jones oxidation and then cleaving the protection with methanolic HCl. This procedure modifies the one disclosed by R. Zhang and J. S. Madalengoitia in J. Org. Chem., 64, pp 330-31 (1999).
US Publication No. US 2005/0020689 A1, herein incorporated by reference, discloses a process for making 3-(amino)-3-cyclobutyl methyl-2-hydroxy-propionamide or a salt thereof, which is an intermediate in the synthesis of compound Z. This publication also claims some intermediates prepared in the synthesis.
US Publication No. US 2005/0059800, herein incorporated by reference, claims an alternative process for preparing the compound of formula Z, which involves using methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid as a starting material.
US Publication No. US 2005/0059684 A1, herein incorporated by reference, prepares esters of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in a process summarized by Scheme 1

EP 0 010 799 (the '799 publication) discloses a process for preparing acid compounds of the formula
where R1 is hydrogen or alkyl and R2 to R7 are, for example, alkyl, from the corresponding imine through a nitrile intermediate. Accordingly, the imine is reacted with a cyanating reagent to form the corresponding nitrile, which is subsequently hydrolyzed to form the acid derivative. The imine derivative is prepared by direct oxidation of a bicyclo-pyrrolidine compound of the formula
or by dehydrohalogenation of the corresponding halo-pyrrolidine derivative of the bicycle-pyrrolidine. The document indicates that the cyanation step forming the nitrile generally leads exclusively to the formation of the trans geometric isomer and this stereochemistry is retained in the hydrolysis step.
U.S. Pat. No. 4,691,022 discloses a process for preparing an acid or ester derivatives of the formula
where R is hydrogen or alkyl and R4 and R5, for example, may form a bicyclic ring system, from the corresponding nitrile. The process comprises converting, with an oxidizing agent in the presence of a silver salt, a pyrrolidine derivative into the corresponding Δ1-pyrrolidine derivative and subsequently reacting the pyrrolidine derivative with HCN, preferably generated by adding a metal cyanide in the presence of mineral acid to the reaction mixture, to form the nitrile. The product is prepared by subjecting the resulting nitrile to solvolysis. The patent does not disclose a process for making a particular isomer of these compounds in a high enantiomeric excess.
None of these foregoing processes provide one particular enantiomer of the bicyclo-pyrrolidine compound in high enantiomeric purity. Accordingly, there remains a need for methods of providing intermediates useful in the synthesis of compounds useful in the treatment or prevention or amelioration of one or more symptoms of hepatitis C. Further, there remains a need for processes providing enantiomeric intermediates which have a prevalence of the desired enantiomer without resorting to arduous enantiomer separation techniques, for example, chiral chromatography.
In view of the importance of hepatitis C virus (“HCV”) protease inhibitors, new, novel methods of making such antagonists are always of interest.